Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

摘要 Galbuimima(GB)生物碱来源于Galbuimima属的树皮， 这是巴布亚新几内亚的传统医学和仪式中的特色。国标生物碱含量 在不同的树木之间差异很大，只有一些树皮样本会导致幻觉。这个 树皮中所含生物碱的数量及其一般稀缺性使鉴定变得复杂 生物分子靶标和严格的药理学特征。在这里，我们描述新的 化学平台采购每一生物碱，首创新的生物靶标 经过三十多年的鉴定和初步的药理学和结构鉴定 生物学。合成平台的生存能力由减少合成负担的路线支持 大约是三倍。 赠款的第一部分展示了克级的Ia/b类生物碱的加入。 通过配体控制的交叉亲电偶联(XEC)。这一策略允许模块化组装 具有各种哌啶侧链的碳环(十氢化氢)核心-定义GB的基序 生物碱。尽管Ia类靶向mAChRs，但Ib类支架的重排改变了GPCR 对OR的选择性。初步数据显示被氧化的类似物向 激动性；活体数据显示大脑迅速渗透到影响老鼠行为的地方。饱满 配体-受体复合体的药理研究及结构表征 开始识别“GB阿片类药物”的独特之处。 第二部分探索了通过HIGH的转化来进行II-IV类分子的克级合成 从芳香族(FAR)支架到高纯度SP3(FSP3)，这是一种立体化学含量丰富的天然产物。 新的交叉偶联反应高效地组装芳烃原料；我们提出了不对称 使现有外消旋路线具有对映体选择性的变体。重要的是，现有的和提议的 路线是高度不同的，允许探索结构变化如何与 人类受体之间的选择性。我们发现另一种高亲和力受体与 抗痉挛生物碱，并建议合成高优先级的缓慢性药物。 这里概述的合成平台与基于细胞的强健秒技术的进展相结合 信使分析现在广泛适用于感兴趣的受体家族，这是前所未有的 能够探测国标生物碱的结构、功能和选择性。最终，我们希望 确定足够的配体-受体对以开始构建GB生物碱-受体相互作用体 在高分辨率实验结构的支持下，预测结构-功能关系。 这项研究具有巨大的潜力，可以为治疗寻找新的特权支架线索 从已经在人类身上验证的植物代谢物发展而来。

Abstract The Galbulimima (GB) alkaloids are derived from the bark of the Galbulimima genus, which features in the traditional medicine and ritual of Papua New Guinea. GB alkaloid content varies markedly among individual trees, and only some bark samples cause hallucination. The number of alkaloids contained in the bark and their general scarcity complicate identification of the biomolecular targets and rigorous pharmacological characterization. Here we describe new chemical platforms for procurement of each Galbulimima alkaloid, the first new biological targets identified in over three decades and preliminary interrogation by pharmacology and structural biology. Viability of the synthetic platform is supported by route that reduce synthetic burden approximately three-fold. The first section of the grant demonstrates gram-scale Class Ia/b GB alkaloid accession by ligand-controlled cross-electrophile coupling (XEC). This strategy allows modular assembly of the carbocyclic (decalin) core with a variety of piperidine side-chains—motifs that define GB alkaloids. Whereas Class Ia targets mAChRs, scaffold rearrangement to Class Ib changes GPCR selectivity to ORs. Preliminary data suggests oxidized analogs shift OR antagonism toward agonism; in vivo data demonstrates rapid penetration of the brain to affect mouse behavior. Full interrogation of pharmacology and structural characterization of ligand-receptor complexes have begun to identify unique aspects of the "GB opioids." The second section explores gram-scale syntheses of Class II–IV via conversion of high fraction aromatic (FAr) scaffolds to high fraction sp3 (Fsp3), stereochemically-rich natural products. New cross-coupling reactions assemble aromatic feedstocks efficiently; we propose asymmetric variants to render existing racemic routes enantioselective. Importantly, existing and proposed routes are highly divergent and allow exploration of how structural variation correlates to selectivity among a human receptors. We identify another high affinity receptor associated with antispasmodic alkaloids and propose the syntheses of high-priority bradycardia agents. The synthetic platform outlined here combined with advances in robust cell-based second messenger assays now widely available for the receptor families of interest allow unprecedented ability to probe structure, function and selectivity of the GB alkaloids. Ultimately, we expect to identify enough ligand-receptor pairs to begin building a GB alkaloid-receptor interactome to predict structure-function relationships, supported by high-resolution experimental structures. This research holds great potential to identify privileged new scaffold leads for therapeutic development from plant metabolites already validated in humans.